Nicotinic Acetylcholine Receptors in Schizophrenia Schizophrenic patients have among the highest rates of tobacco smoking and nicotine is thought to alleviate some of the symptoms associated with schizophrenia. Chronic nicotine exposure up regulates nicotinic agonist binding to brain nicotinic acetyl choline receptors (nAChR). In postmortem studies, there are region-specific increases in high affinity nAChR binding in healthy human tobacco smokers but not in schizophrenic smokers. While these data suggest high affinity nAChR dysregulation in schizophrenic smokers, there are no in vivo data showing nAChR dysregulation in schizophrenia or how it might relate to smoking or the symptoms (cognitive deficits) associated with schizophrenia. Using [123I]5-IA-85380 (5-IA) and SPECT imaging we have recently shown that consistent with post mortem data, healthy smokers have 30% higher 22-nAChR availability vs. never smokers. Consistent with post-mortem studies in our pilot data schizophrenic smokers (SS) (n=7;6 medicated and 1 unmedicated) show region specific reductions in brain [123I]5-IA uptake relative to healthy smokers (HS) regardless of medication status. These findings may reflect a failure to upregulate 22-nAChR in schizophrenic smokers. Further, SS show higher [123I]5-IA uptake compared to healthy never smokers (HNS) while schizophrenic nonsmokers (SNS) (n=4) show lower [123I]5-IA uptake in the thalamus, but also in the parietal, frontal, and occipital cortices compared to HNS. Memory and attention were disrupted by smoking abstinence and restored by the resumption of smoking. Aims: Using SPECT and 5-IA, this proposal aims to determine if 1A) SS show reduced region specific 22- nAChR availability relative to HS;1B) unmedicated SS show reduced region specific 22-nAChR availability relative to HNS;1C) there are differences in 22-nAChR availability between medicated and unmedicated SS;2) SNS show lower 22-nAChR availability compared to HNS. In addition we plan to explore 1) differences in regional 22 nAChR availability between medicated SS vs. medicated SNS;2) the relationship between cognitive test performance and regional 22-nAChR availability;and 3) the effects of smoking abstinence and smoking resumption on cognitive test performance. Methods: HS and SS (medicated and unmedicated) will achieve 5 days of confirmed abstinence with a combined strategy of counseling and contingency management, and hospitalization for only the schizophrenic smokers. Matched HNS and SNS will also be studied. All subjects will be studied using SPECT and 5-IA followed by an MRI for coregistration. Cognitive testing (verbal memory, attention, working memory and selective attention) will be assessed while smoking as usual, 24 hours after quitting, 5 days abstinence and if subjects resume smoking. Cognitive data will be correlated with regional brain [123I]5-IA uptake (VT and VT'). PUBLIC HEALTH RELEVANCE There are high rates of smoking in individuals with schizophrenia and smoking (nicotine) may alleviate certain symptoms of schizophrenia. This has led to the suggestion that alterations in the nicotine receptor system may contribute to the high rates of smoking (addiction) in schizophrenia and some of its symptoms. This grant application proposes to use brain imaging to study the nicotine receptor system in schizophrenia.